The ETS proteins are transcription factors that contain separate DNA- binding and transactivation domains. ETS proteins bind to a purine-rich binding sequence (EBS) present in a large number of promoters and enhancers. A number of the ets genes (ETS1, ERGB/Hu-FLI-1, PU.1/Spi-1, ERG, and ELF1) encode tissue-specific proteins, primarily expressed in cells of hematopoietic lineage. PU.1 has been shown to activate transcription from immunoglobulin ~ 3' and major histocompatibility complex (MHC) class II enhancers. ETS1 and ETS2 bind to and transactivate transcription from HTLV-1 long terminal repeat (LTR) and polyoma enhancer. ETS proteins also transactivate transcription via binding to murine sarcoma virus (MSV) LTR and GATA-1 promoter. ELF1, on the other hand, regulates transcription of the IL-2 gene in T-cells. Dimerization between two different ETS family proteins has not been reported; however, they have been shown to interact with other factors. The human immunodeficiency viruses (HIV-1 and HIV-2) belong to a group of lentiviruses and are the etiological agents of the acquired immunodeficiency syndrome (AIDS). The replication of both HIV-1 and HIV- 2 viruses is dependent on cis-regulatory sequences located in the LTR region. The HIV-1 LTR contains a core enhancer located at -79 to -109, which consists of a 10-bp direct repeat (GGGACTTTCC) and this sequence has been shown to be responsible for activation of HIV-1 mRNA in T-cells by ETS family proteins. By examining the HIV-2 LTR sequence around the mRNA start site, we have been able to identify three possible ETS-binding sites (EBS), which may interact with ETS family proteins to effect HIV-2 mRNA regulation. In the present study, we have analyzed the binding of those sites with the baculovirus-expressed human ETS1 protein. In addition, we have constructed vectors that contain point mutations in the phosphorylation sites of the ETS1 protein and investigated the role of phosphorylation on activation of HIV-1 LTR.